Virtually all eukaryotic organisms appropriately examined have been shown to possess the capacity for endogenous temporal control and organization known as a circadian rhythm. The cellular machinery responsible for generating rhythms is collectively known as the biological clock. A healthy circadian clock underlies both physical and mental health. Because of the ubiquity of its influence on human mental and physiological processes - from circadian changes in basic human physiology to the clear involvement of rhythms in work/rest cycles and sleep - understanding the clock is basic to prevention and treatment of many physical and mental illnesses. [unreadable] [unreadable] Our specific aims are designed to further our understanding of the means through which the clock regulates cell behavior, including cell growth and in some cases cancer. Specific Aim #1 builds upon our identification of the cell cycle regulator checkpoint kinase 2 as a conditional modifier of clock function in Neurospora. We will pursue this work in mammalian cells in culture and in mice to probe the interconnectedness of the circadian system and cell cycle. Specific Aim #2 builds upon our ongoing analysis of non-circadian output oscillators in Neurospora as an important means of mediating circadian output. We will identify components of output oscillators and determine the means through which they are connected to the circadian cycle. Specific Aim #3 builds upon our strong grounding in genomics. We will carry out an overexpression screen and a knockout screen for components of output oscillators and will use microarrays to identify the clock-controlled and output oscillator-controlled genes in Neurospora. [unreadable] [unreadable] Our long term goals are to describe, in the language of genetics and biochemistry, the feedback cycle comprising the circadian clock, how this cycle is synchronized with the environment, and how time information generated by the feedback cycle is used to regulate the behavior of cells and organisms. These projects are complementary and mutually enriching in that they rely on genetic and molecular techniques to dissect, and ultimately to understand, the organization of the cell as a function of time. PUBLIC HEALTH RELEVANCE: Virtually all eukaryotic organisms appropriately examined have been shown to possess the capacity for endogenous temporal control and organization known as a circadian rhythm, the output of a biological clock. A healthy circadian clock underlies both physical and mental health. Because of the ubiquity of its influence on human mental and physiological processes - from circadian changes in basic human physiology to the clear involvement of rhythms in work/rest cycles and sleep - understanding the clock is basic to prevention and treatment of many physical and mental illnesses. [unreadable] [unreadable] [unreadable]